Abstract
Apoptosis is deregulated in most, if not all, cancers, including hematological malignancies. Smac mimetics that antagonize Inhibitor of Apoptosis (IAP) proteins have so far largely been investigated in acute myeloid leukemia (AML) cell lines; however, little is yet known on the therapeutic potential of Smac mimetics in primary AML samples. In this study, we therefore investigated the antileukemic activity of the Smac mimetic BV6 in diagnostic samples of 67 adult AML patients and correlated the response to clinical, cytogenetic and molecular markers and gene expression profiles. Treatment with cytarabine (ara-C) was used as a standard chemotherapeutic agent. Interestingly, about half (51%) of primary AML samples are sensitive to BV6 and 21% intermediate responsive, while 28% are resistant. Notably, 69% of ara-C-resistant samples show a good to fair response to BV6. Furthermore, combination treatment with ara-C and BV6 exerts additive effects in most samples. Whole-genome gene expression profiling identifies cell death, TNFR1 and NF-κB signaling among the top pathways that are activated by BV6 in BV6-sensitive, but not in BV6-resistant cases. Furthermore, sensitivity of primary AML blasts to BV6 correlates with significantly elevated expression levels of TNF and lower levels of XIAP in diagnostic samples, as well as with NPM1 mutation. In a large set of primary AML samples, these data provide novel insights into factors regulating Smac mimetic response in AML and have important implications for the development of Smac mimetic-based therapies and related diagnostics in AML.
Highlights
Acute myeloid leukemia (AML) is a genetically heterogeneous disease with a multi-step pathogenesis [1]
second mitochondriaderived activator of caspases (Smac) mimetics that antagonize Inhibitor of Apoptosis (IAP) proteins have so far largely been investigated in acute myeloid leukemia (AML) cell lines; little is yet known on the therapeutic potential of Smac mimetics in primary AML samples
We report that about half of the 67 investigated primary AML samples at diagnosis are sensitive to the Smac mimetic BV6 including about two thirds of ara-C-resistant cases, while mononuclear cells from healthy donors remain largely unaffected
Summary
Acute myeloid leukemia (AML) is a genetically heterogeneous disease with a multi-step pathogenesis [1]. Many chromosomal aberrations have been identified, which alter normal gene function or expression, thereby contributing to leukemic transformation. Many of these cytogenetic aberrations provide important diagnostic and prognostic information [3]. Apoptosis is one of the best characterized forms of programmed cell death, which is typically deregulated in most, if not all, cancers [7]. Since most current chemotherapeutic strategies depend on intact cell death signaling within cancer cells for their cytotoxic effects, deregulation of cell death programs can lead to treatment resistance [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
